Human Molecular Genetics, Vol 6, 2155-2161, Copyright © 1997 by Oxford University Press
AC Jones, CE Daniells, RG Snell, M Tachataki, SA Idziaszczyk, M Krawczak, JR Sampson and JP Cheadle
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by
the development of hamartomatous growths in many organs. Sixty to seventy
percent of cases are sporadic and appear to represent new mutations. TSC
exhibits locus heterogeneity: the TSC2 gene is located at 16p13.3 whilst
the TSC1 gene, predicted to encode a novel protein termed hamartin, has
recently been cloned from 9q34. With the exception of a contiguous gene
deletion syndrome involving TSC2 and PKD1 , TSC1 and TSC2 phenotypes have
been considered identical. We have now comprehensively defined the TSC1
mutational spectrum in 171 sequentially ascertained, unrelated TSC patients
by single strand conformation polymorphism and heteroduplex analysis of all
21 coding exons, and by assaying a restriction fragment spanning the whole
locus. Mutations were identified in 9/24 familial cases, but in only 13/147
sporadic cases. In contrast, a limited screen revealed TSC2 mutations in
two of the familial cases and in 45 of the sporadic cases. Thus TSC1
mutations were significantly under-represented among sporadic cases
(Fisher's exact p -value = 3.12 x 10(-4)). Both large deletions and
missense mutations were common at the TSC2 locus whereas most TSC1
mutations were small truncating lesions. Mental retardation was
significantly less frequent among carriers of TSC1 than TSC2 mutations
(odds ratio 5.54 for sporadic cases only, 6.78 +/- 1.54 when a single
randomly selected patient per multigeneration family was also included). No
correlation between mental retardation and the type of mutation was found.
We conclude that there is a reduced risk of mental retardation in TSC1 as
opposed to TSC2 disease and that consequent ascertainment bias, at least in
part, explains the relative paucity of TSC1 mutations in sporadic TSC.
ARTICLES
Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis
Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN, UK.
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